The cyclooxygenase-2 (COX-2) enzyme is commonly overexpressed in epithelial cancers and is associated with a poor prognosis in breast and other malignancies. Epidemiological studies show that chronic use of COX inhibitors is associated with a lower risk of primary breast, colon, lung and other cancers. Our long term goal is to develop therapies that will prevent or treat metastatic breast cancer. We have employed preclinical and clinical models to define the factors that contribute to tumor metastasis. Our studies show that COX-2 activity contributes to aggressive breast cancer behavior and that COX-2 inhibitors control tumor growth and metastasis by immune-dependent mechanisms. Preliminary studies support the hypothesis that COX inhibitors alter intrinsic properties of tumor cells, altering the balance of stimulating and inhibiting ligands that engage receptors on immune effector cells. These modulations render the tumor target more sensitive to immune cell-mediated lysis. Using pharmacologic and genetic approaches, Aim 1 will determine the functional significance of Natural Killer-ligand modulations. The COX-2 product PGE2 mediates cellular responses by signaling through four EP receptors. Our studies indicate a novel approach to inhibit breast cancer metastasis by targeting selective EP receptors. The second Aim will continue to identify the relevant EP receptor pathways that modulate metastatic behavior and NK activities. The third Aim will define the role of EP receptors expressed by tumor and host cells in localized breast cancer. Using a large series of well-characterized human breast tumors, for which long term survival is known, the fourth Aim will determine if EP receptors or NK ligand expression have relevance to the behavior of human breast cancers. These studies will test the hypothesis that expression of NK-activating ligands is associated with a better prognosis but the presence of some EP receptors indicates a worse outcome. Recent advances in the treatment of breast cancer have greatly improved the outlook for women with hormone-dependent disease. Fewer treatment options are available for hormone-independent and advanced disease. Immune-based therapies are attractive alternatives to existing therapies and the proposed studies may identify a strategy that would boost both innate and adaptive arms of the antitumor immune response.